A process for making a beta methyl carbapenem intermediate is disclosed. A compound of formula I: ##STR6##
is contacted in a non-reactive solvent with methyl Meldrum's acid and a base to produce a compound of formula III: ##STR7##
Compound III is treated in an aprotic solvent with a scavenging base, an alkali metal halide and a tri-organo silyl protecting compound for nitrogen to produce a compound of formula IV: ##STR8##
Compound IV may be reacted with a nucleophile Nu--X in a non-reactive solvent and base, and the mixture acidified to produce a compound of formula V. ##STR9##
Compound V may be reacted with mild acid to produce a compound of formula VI. ##STR10##
Numerous routes to beta-methyl carbapenem intermediates of formula VI have been cited in the literature: ##STR11##
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Previous methods to stereoselectively prepare .beta.-methyl carbapenems include:
(1) hydrogenation of a 4-(2-propenyl) substituted azetidinone. PA1 (2) stereoselective protonation of an enolate ion. PA1 (3) reaction of 4-acetoxy azetidinone with a chiral enolate. PA1 R is PA1 P' is a nitrogen protecting group such as tri-organo-silyl, including tri-C.sub.1-4 alkylsilyl, phenyl di C.sub.1-4 alkyl silyl and diphenyl mono C.sub.1-4 alkyl silyl including tert-butyl-dimethylsilyl; and isopropyldimethyl-silyl; comprising: PA1 R.sup.1 is
These methods required difficult multistep preparation of intermediates (1) and/or reagents (3), tedious manipulation of highly reactive intermediates at low temperature (2), or the use of expensive reagents (2,3).
The invention disclosed herein provides a versatile route to .beta.-methyl intermediates (VI Scheme 1 with high stereoselectivity from readily available starting materials in four steps.